Naphthyloxazolidone derivatives

ABSTRACT

A naphthyloxazolidone derivative of the formula: &lt;CHEM&gt; wherein R&lt;1&gt; is hydrogen atom, hydroxy group, nitro group, amino group, sulfo group, aminosulfonyl group, a lower alkenyloxy group, a lower alkynyloxy group, a mono or di(lower alkyl)aminocarbonyloxy group, a lower alkanoyloxy group or a lower alkoxy group which may have a substituent selected from an aryl group, a cycloalkyl group, an oxygen-containing heteromonocyclic group, hydroxy group, a lower alkoxy group, cyano group, a di(lower alkyl)amino group, aminocarbonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxy group, a lower alkylthio group, a lower alkylsulfinyl group and a lower alkylsulfonyl group; R&lt;2&gt; is hydroxy group, a lower alkoxy group, a lower alkylsulfonyloxy group, triazo group or an amino group which may have a substituent selected from a lower alkyl group and a lower alkanoyl group, and a pharmaceutically acceptable salt thereof are disclosed. Said derivative and a pharmaceutically acceptable salt thereof lare useful as an antidepressant.

This invention relates to novel naphthyloxazolidone derivatives whichare useful as an antidepressant and processes for preparing the same.

Monoamine oxidase (MAO), which catalyzes oxidative deamination ofmonoamines to produce aldehydes, is classified into two groups (i.e.,MAO-A and MAO-B) according to its substrate specificity. MAO-A catalyzesoxidative deamination of neurotransmitters such as serotonin,noradrenaline and the like, whereas MAO-B catalyzes oxidativedeamination of phenethylamine, and the like.

Known MAO inhibitors which have been used as an antidepressant have noselective inhibitory activity against MAO-A or MAO-B and showirreversible and long-lasting inhibitory activity. Therefore, the knownMAO inhibitors are disadvantageous in that they have side effects suchas hepatic injuries, migraine and hypertensive crises after theingestion of tyramine-containing food, i.e., cheese effect.

An object of the present invention is to provide novelnaphthyloxazolidone derivatives which have potent reversible andselective inhibitory activity against MAO-A and are useful as anantidepressant.

Another object of the present invention is to provide processes forpreparing said naphthyloxazolidone derivatives.

Another object of the present invention is to provide novelintermediates of said naphthyloxazolidone derivatives.

The present invention relates to a naphthyloxazolidone derivative of theformula: ##STR2## wherein R¹ is hydrogen atom, hydroxy group, nitrogroup, amino group, sulfo group, aminosulfonyl group, a lower alkenyloxygroup, a lower alkynyloxy group, a mono or di(loweralkyl)aminocarbonyloxy group, a lower alkanoyloxy group or a loweralkoxy group which may have a substituent selected from an aryl group, acycloalkyl group, an oxygen-containing heteromonocyclic group, hydroxygroup, a lower alkoxy group, cyano group, a di(lower alkyl)amino group,aminocarbonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxygroup, a lower alkylthio group, a lower alkylsulfinyl group and a loweralkylsulfonyl group; R² is hydroxy group, a lower alkoxy group, a loweralkylsulfonyloxy group, triazo group or an amino group which may have asubstituent selected from a lower alkyl group and a lower alkanoylgroup, or a pharmaceutically acceptable salt thereof.

Examples of the naphthyloxazolidone derivative (I) of the presentinvention include those of the formula (I) in which an aryl group isphenyl group, a cycloalkyl group is a cycloalkyl group of 3 to 6 carbonatoms, and an oxygen-containing heteromonocyclic group is atetrahydrofuryl group. Among them, preferred compounds include those ofthe formula (I) in which R¹ is a lower alkenyloxy group, a loweralkanoyloxy group or a lower alkoxy group which may have a substituentselected from cyclopropyl group, hydroxy group and cyano group; R² is alower alkoxy group. More preferred compounds are those of the formula(I) in which R¹ is a lower alkoxy group which may have a substituentselected from cyclopropyl group and cyano group. Another preferredcompounds are those of the formula (I) in which R¹ is at the 6-positionof naphthalene ring and the 5-substituted-2-oxazolidon-3-yl group is atthe 2-position of naphthalene ring.

According to the present invention, the naphthyloxazolidone derivatives(I) can be prepared either by

[A] reacting a lower alkyl naphthylcarbamate compound of the formula:##STR3## wherein R³ is a lower alkyl group and R¹ is the same as definedabove, or a salt thereof with an oxirane compound of the formula:##STR4## wherein R² is the same as defined above, or a salt thereof, orby

[B] reacting a naphthalene compound of the formula: ##STR5## wherein X¹is a reactive residue, R¹ is the same as defined above, or a saltthereof with a 2-oxazolidone compound of the formula: ##STR6## whereinR² is the same as defined above, or a salt thereof.

The naphthyloxazolidone derivative of the formula: ##STR7## wherein R¹is the same as defined above, can also be prepared by

[C] condensing a propanediol compound of the formula: ##STR8## whereinR¹ is the same as defined above, or a salt thereof with a carbonylcompound of the formula:

    CO(X.sup.2).sub.2                                          (VII)

wherein X² is a reactive residue.

The naphthyloxazolidone derivative of the formula: ##STR9## wherein R⁴is a lower alkyl group or a lower alkylsulfonyl group, and R¹ is thesame as defined above, can also be prepared by

[D] condensing the compound (I-a) with the compound of the formula:

    R.sup.4 --X.sup.3                                          (VIII)

wherein X³ is a reactive residue and R⁴ is the same as defined above.

The naphthyloxazolidone derivative of the formula: ##STR10## wherein R²is the same as defined above, can also be prepared by

[E] reducing the compound of the formula: ##STR11## wherein R⁵ is anaryl-lower alkyl group, R² is the same as defined above, or a saltthereof.

Further, the naphthyloxazolidone derivative of the formula: ##STR12##wherein R⁶ is a lower alkenyl group, a lower alkynyl group, a mono ordi(lower alkyl)aminocarbonyl group, a lower alkanoyl group or a loweralkyl group which may have a substituent selected from an aryl group, acycloalkyl group, an oxygen-containing heteromonocyclic group, hydroxygroup, a lower alkoxy group, cyano group, a di(lower alkyl)amino group,aminocarbonyl group, a lower alkoxycarbonyl group, a lower alkanoyloxygroup, a lower alkylthio group, a lower alkylsulfinyl group and a loweralkylsulfonyl group, R² is the same as defined above, can also beprepared by

[F] condensing the compound (I-c) or a salt thereof with a compound ofthe formula:

    R.sup.6 --X.sup.4                                          (IX)

wherein X⁴ is a reactive residue, R⁶ is the same as defined above, or asalt thereof.

Among the naphthyloxazolidone derivative (I-e), a compound of theformula: ##STR13## wherein R⁷ is cyano group or a lower alkoxycarbonylgroup, and R² is the same as defined above, can also be prepared by

[G] reacting a compound (I-c) or a salt thereof with a compound of theformula:

    R.sup.7 --CH═CH.sub.2                                  (X)

wherein R⁷ is the same as defined above.

Further, among the naphthyloxazolidone derivative (I-e), a compound ofthe formula; ##STR14## wherein R⁸ is a lower alkyl group, and R² is thesame as defined above, can also be prepared by

[H] reacting the compound (I-c) or a salt thereof with a lower alkylisocyanate.

The reaction of the compound (II) with the compound (III) (i.e., Step[A]) can be carried out in the presence of a base. Any conventional basemay be used for this reaction. Preferred examples of the base include atri(lower alkyl)amine, a 4-di(lower alkyl)aminopyridine, an alkali matalhydroxide, an alkali metal alkoxide and the like. The reaction may becarried out in the presence or absence of a solvent such asdimethylformanide, dimethylacetamide, dimethylsulfoxide, xylene or thelike. It is preferred to carry out the reaction under heating, forexample, at a temperature between 50° and 150° C., preferably at atemperature between 90° and 110° C.

The reaction of the compound (IV) with the compound (V) (i.e., Step [B])can be carried out in the presence of an acid acceptor. Examples of theacid acceptor include conventional organic or inorganic bases such as analkali metal bicarbonate, an alkali metal carbonate, an alkali metalhydride, a tri(lower alkyl)amine and so forth. Examples of the reactiveresidue (X¹) of the compound (IV) include a conventional reactiveresidue such as a halogen atom and the like. The reaction may be carriedout in the presence or absence of a solvent such as dimethylformanide,dimethylacetamide, dimethylsulfoxide, xylene or the like. It ispreferred to carry out the reaction under heating, for example, at atemperature between 150° and 220° C. In particular, said reactionprefelably proceeds by adding copper power to the reaction system.

The condensation reaction of the compound (VI) with the compound (VII)(i.e., Step [C]) can be carried out in the presence of a base. The samebases as mentional in Step [A] are preferably used for the reaction.Examples of the reactive residue (X²) of the compound (VII) include anlower alkoxy group, imidazolyl group, halogen atom and the like. It ispreferred to carry out the reaction in a solvent such as toluene,xylene, methylen chloride, chloroform, tetrahydrofuran and so forth andat room temperature or under heating, for example, at a temperaturebetween 10° and 150° C.

The condensation reaction of the compound (I-a) with the compound (VIII)(i.e., Step [D]) can be carried out in the presence or absence of anacid acceptor. The same bases as mentioned in Step [B] are preferablyused for the reaction as the acid acceptor. Examples of the reactiveresidue (X³) of the compound (VIII) include a halogen atom, a loweralkanoyloxy group, a (lower alkyl) sulfonyloxy group, arylsulfonyloxygroup and the like. It is preferred to carry out the reaction in asolvent such as acetone, ethyl acetate, N,N-dimethylformamide,tetrahydrofuran, methylene chloride, diethyl ether, dioxane or the like.Said reaction preferably proceeds at room temperature or under heating,for example, at a temperature between 30° and 120° C.

The reduction of the compound (I-d) (i.e., Step [E]) can be conducted ina conventional manner. For example, said reduction is carried out bysubjecting the compound (I-d) to catalytic hydrogenation in the presenceof palladium-carbon, Raney nickel, Raney cobalt, platinum, rhodium, orthe like. The catalytic hydrogenation preferably proceeds in a solventsuch as tetrahydrofuran, dioxane, a lower alkanol or the like, underatmospheric pressure or increased pressure and at room temperature orunder warming, for example, at a temperature between 10° and 50° C.

The condensation reaction of compound (I-c) with the compound (IX)(i.e., Step [F]) can be carried out in the presence or absence of anacid acceptor. The same organic or inorganic bases as mentioned in Step[B] are prefelably used for the reaction as the acid acceptor. Examplesof the reactive residue (X⁴) includes the same as the reactive residue(X³). It is preferred to carry out the reaction in a solvent such asacetone, ethyl acetate, dimethylformamide, dimethylsulfoxide or the likeand at room temperature or heating, for example, at a temperaturebetween 30° and 120° C.

The reaction of the compound (I-c) with the compound (X) (i.e., Step[G]) and the reaction of the compound (I-c) with the lower alkylisocyanate (i.e., Step [H]) can be carried out in the presence of abase. The same bases as mentioned in Step [A] are prefelably used forthe reaction, and in addition, benzyltri(lower alkyl)ammonium hydroxide,tetra(lower alkyl)ammonium hydroxide and the like can also be used. Thereaction preferably proceeds in a solvent such as tetrahydrofuran,methylene chloride, dimethylformamide, dimethylsulfoxide or the like andat room temperature or under heating, for example, at a temperaturebetween 20° and 80° C.

In the above-mentioned reactions, the starting compounds of the presentinvention may be used either in a free form or in the form of a salt.For example, the compounds (VI), (I-a) and (I-c), and the compounds (II)to (V), (IX) and (I-d) which have hydroxy group are, if required, usedin the form of an alkali metal salt, an alkali earth metal salt, anammonium salt and the like. On the other hand, the compounds (V) and(VI), and the compounds (II) to (IV), (IX), (I-a), (I-c) and (I-d) whichhave amino group or mono or di(lower alkyl)amino group are, if required,used in the form of an organic or inorganic acid addition salt.

Concomitantly, some of the naphthyloxazolidone derivative (I) of thepresent invention can, if required, be converted into anothernaphthyloxazolidone derivative (I) in a conventional manner. Forexample, when R¹ is nitro group and/or R² is triazo group, said group(s)may be converted into amino group(s) by catalytic hydrogenation. Ifrequired, the resulting amino group(s) may be converted into a loweralkanoylamino group(s), or may be converted into hydroxy group(s) or alower alkoxy group(s) after diazotization of said amino group(s). WhenR¹ is sulfo group, said group may be converted into aminosulfo group bya conventional amination. Further, when R¹ is a (loweralkyl)thio-substituted-lower alkoxy group, said group may be convertedinto a (lower alkyl)sulfinyl-substituted-lower alkoxy group or a (loweralkyl)sulfonyl-substituted-lower alkoxy group by oxidation therof. Onthe other hand, when R² is a lower alkoxy group, said group may beconverted into hydroxy group by hydrolysis thereof, and if required, beconverted into a lower alkylsulfonyloxy group in a conventional manner,and if necessary, further converted into a lower alkylamino group or atriazo group.

The naphthyloxazolidone derivatives (I) of the present invention includewithin its scope either one of optically active isomers and the mixturesthereof. Since the reactions of the present invention as mentioned aboveproceed without accompanying racemization, the compound (I) can beobtained as an optically active compound by using an optically activestarting materials.

Further, when the naphthyloxazolidone derivative (I) is in the form of aracemic modification, it can be separated into each of two opticallyactive isomers thereof in a conventional manner, for example, by thesteps of:

(1) treating said compound (I) with an alkali metal hydroxide (e.g.,potassium hydroxide),

(2) protecting the amino group of the resultant compound with a loweralkoxycarbonyl group,

(3) reacting the resultant compound with an optically active1-(2-naphthylsulfonyl)pyrrolidin-2-carbonyl chloride,

(4) separating each of two kinds of resulting diastereomers by takingadvantage of difference in solubilities thereof or columnchromatography,

(5) hydrolyzing each of the diastereomers with an alkali metal hydroxide(e.g., sodium hydroxide), and then,

(6) reacting the resultant compound with compound (VII) in the samemanner as described in Step [C].

The naphthyloxazolidone derivatives (I) can be used for pharmaceuticaluse either in a free form or in the form of a pharmaceuticallyacceptable salt. Examples of the pharmaceutically acceptable saltsinclude salts with an organic or inorganic base such as alkali metalsalts (e.g., sodium salt, potassium salt), alkaline earth metal salts(e.g., calcium salt, magnesium salt), ammonium salt and the like, andorganic or inorganic acid addition salts such as hydrochloride, sulfate,acetate, benzensulfonate and the like.

The naphthyloxazolidone derivative (I) or a pharmaceutically acceptablesalt thereof has excellent reversible and selective MAO-A inhibitoryactivity. Accordingly, the compound (I) or a pharmaceutically acceptablesalt thereof is useful as a therapeutic or prophylactic agent fordepressive conditions such as depression, senile depression, abulia,axiety, insomnia, anorexia and the like in warm-blood animals includinghuman beings. In particular, the compound (I) or a pharmaceuticallyacceptable salt thereof is characterized in that it shows short durationof inhibitory activity and has no side effect such as hepatic injuries,migraine, cheese effect or the like. Moreover, the compound (I) or apharmaceutically acceptable salt thereof is low in toxicity and havehigh safety as a pharmaceuticals. For example, when3-(6-cyanoethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone wasadministered orally to mice at a dose of 2 g/kg, no mice died during 2week-observation period.

The naphthyloxazolidone derivative (I) or a pharmaceutically acceptablesalt thereof may be administered either orally or parenterally. They mayalso be used in the form of pharmaceutical preparations such as tablets,capsules, powders, granules, injections and the like, if necessary, inadmixture with a pharmaceutically acceptable carrier, diluent ordisintegrant.

The dose of the naphthyloxazolidone derivative (I) or a pharmaceuticallyacceptable salt thereof may vary depending on the age, body weight andcondition of patients, the kind and severity of diseases to be treated,administration route, etc, but it may usually be in the range of about0.01 to about 250 mg per kg, preferably about 0.1 to about 30 mg per kg,per day.

Among the starting compounds of the present invention, the compounds(II), (V) and (VI) are novel. The compound (II) may be prepared, forexample, by reacting a naphthylamine compound of the formula: ##STR15##wherein R¹ is the same as defined above, with a compound of the formula:

    X.sup.5 --COOR.sup.3                                       (XII)

wherein X⁵ is halogen atom and R³ is the same as defined above in thepresence of an acid acceptor (e.g., sodium bicarbonate) and in a solvent(e.g., methylene chloride). The compound (V) may be prepared, forexample, by reacting an aminopropanol compound of the formula: ##STR16##wherein R² is the same as defined above, with a benzyloxycarbonyl halideor a lower alkoxy-carbonyl halide in the presence of an acid acceptor(e.g., triethylamine) and in a solvent (e.g., tetrahydrofuran), andthen, subjecting the resultant compound to intermolecular cyclization inthe presence of a base (e.g., sodium hydride). Furthermore, the compound(VI) may be prepared, for example, by reacting the naphthylaminecompound (XI) with 2,2-dimethyl-4-tosyloxy-1,3-dioxolane, and then,hydrolyzing the resultant compound in the presence of an acid (e.g.,hydrochloric acid).

In this specification and Claims, the terms "a lower alkyl group", "alower alkoxy group", "a lower alkanoyl group", "a lower alkenyl group"and "a lower alkynyl group" represent an alkyl group of one to 6 carbonatoms, an alkoxy group of one to 6 carbon atoms, an alkanoyl group of 2to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms and analkynyl group of 2 to 6 carbon atoms, respectively.

EXPERIMENT 1 Inhibitory effect against MAO-A activity of cerebralmitochondorian fraction from rat (in vitro) Method

A suspension (7 mg protein/ml) of mitochondorial fraction obtained fromcerebral tissue of rats in a conventional manner was used as a sample ofenzyme, and serotonin was used as the substrate. of MAO-A. The MAO-Aactivity was estimated in terms of the amount of ammonia produced fromserotonin by the enzymatic reaction.

Inhibitory rate of the test compounds (10⁻⁷ M) against the MAO-Aactivity was calculated according to the following equation. ##EQU1##NH₃ (T): the amount of NH₃ in test tube (addition of test compound)

NH₃ (C): the amount of NH₃ in control tube (no addition of testcompound).

Results

The results are shown in the following Table 1.

                  TABLE 1                                                         ______________________________________                                         ##STR17##               Inhibitory rate (%) against                          R.sup.1                 MAO-A activity                                        ______________________________________                                        H                       78.4                                                  OCH(CH.sub.3).sub.2     98.8                                                  O(CH.sub.2).sub.2 CN    98.1                                                  O(CH.sub.2).sub.3 CN    95.5                                                   ##STR18##              93.5                                                  O(CH.sub.2).sub.3 OH    91.7                                                  OCH.sub.2 CHCH.sub.2    96.8                                                  OCOCH.sub.3             76.6                                                  ______________________________________                                    

EXPERIMENT 2 Inhibitory effect against cerebral MAO-A and MAO-B activityin mouse. Method

A test compound (30 mg/kg) suspended in 0.5% aqueous sodiumcarboxymethylcellulose (CMC-Na) solution was administered orally to agroup of 3 mice. The brain was excised 45 minutes after theadministration. A control group was administered with the 0.5% aqueousCMC-Na solution alone.

The brain tissue was homogenized in 9 volumes of ice-cold distilledwater and the homogenate was used as enzyme. MAO-A activity wasestimated in the same manner as described in Experiment 1, whereas MAO-Bactivity was estimated in terms of the amount of benzaldehyde formedfrom benzylamine according to the method as described in "The Journal ofLaboratory and Clinical Medicine, Vol. 62, P.P. 766-776 (1963)".

Inhibitory rate of the test compound against the MAO-B activity arecalculated according to the following equation. ##EQU2## BA(T): theamount of benzaldehyde in the medicated group BA(C): the amount ofbenzaldehyde in the non-medicated control group.

Results

The results are shown in the following Table 2.

                  TABLE 2                                                         ______________________________________                                         ##STR19##              Inhibitory rate (%)                                   R1                     MAO-A    MAO-B                                         ______________________________________                                        OCH(CH.sub.3).sub.2     86.8 ±                                                                              3.6 ±                                                             5.4      5.3                                          O(CH.sub.2).sub.2 CN   109.2 ±                                                                             -1.0 ±                                                             3.5      2.3                                          O(CH.sub.2).sub.3 CN    99.8 ±                                                                             -1.9 ±                                                             16.1     4.8                                           ##STR20##              71.4 ±  4.3                                                                        -4.5 ±  5.9                                O(CH.sub.2).sub.3 OH    57.1 ±                                                                              1.0 ±                                                             4.3      0.8                                          OCOCH.sub.3             56.4 ±                                                                             -3.1 ±                                                             7.4      1.8                                          (positive control)                                                            pargyline               42.0 ±                                                                              98.3 ±                                                            2.4      5.9                                          ______________________________________                                    

EXAMPLE 1

(1) A mixture of 16.7 g of ethoxycarbonyl chloride and 20 ml ofmethylene chloride is added dropwise to a mixture of 20.0 g of2-naphthylamine, 17.6 g of sodium bicarbonate, 100 ml of water and 200ml of methylene chloride under ice-cooling and stirring. The mixture isstirred overnight at room temperature. Chloroform is added to themixture and the organic layer is separated, dried and treated withcharcol. The residue is recrystallized from ethyl acetate-hexane to give25.26 g of N-ethoxycarbonyl-2-naphthylamine.

m.p. 69.0°-70.5° C.

(2) A mixture of 3.82 g of the product obtained in the the paragraph(1), 3.13 g of 2-(methoxymethyl)oxirane and 0.4 g of triethylamine isrefluxed for 3.5 hours. The reaction mixture is extracted with ethylacetate. The extract is washed with water, dried and filtered. Thefiltrate is condensed and the residue is purified by silica gel columnchromatography [solvent: ethyl acetate-hexane (2:3)] to give 3.75 g ofcrude 5-methoxymethyl-3-(2-naphthyl)-2-oxazolidone. Therecrystallization of this crude product from ethyl acetate-hexane gives3.17 g of colorless needles.

m.p. 79.5°-81.5° C.

EXAMPLE 2 to 5

(1) The corresponding starting compounds are treated in the same manneras described in Example 1-(1) to give compounds shown in Table 3.

                  TABLE 3                                                         ______________________________________                                         ##STR21##                                                                    Compound (II-a)                                                               Ex. No.                                                                              R.sup.1  position*                                                                              Physical Properties                                  ______________________________________                                        2-(1)  7-NO.sub.2                                                                             2        m.p. 143-144° C.                                                       (ethyl acetate - hexane)                             3-(1)  5-OH     2        m.p. 117-121° C.                                                       (ethyl acetate - isopropyl ether -                                            hexane)                                              4-(1)  6-SO.sub.3 Na                                                                          2        m.p. >320° C.                                                          (isopropyl ether - water)                                                     IR.sub.Max.sup.Nujol (cm.sup.-1): 3270, 1700         5-(1)  H        1        m.p. 80.5-81° C.                                                       (ethyl acetate - hexane)                             ______________________________________                                         *A position of NHCO.sub.2 C.sub.2 H.sub.5 in naphthalene ring            

(2) The products obtained in the paragraph (1) are treated in the samemanner as described in Example 1-(2) to give compounds shown in Table 4

                  TABLE 4                                                         ______________________________________                                         ##STR22##                                                                     ##STR23##                                                                    Compound (I-f)                                                                Ex. No.                                                                              R.sup.1  position*                                                                              Physical Properties                                  ______________________________________                                        2-(2)  7-NO.sub.2                                                                             2        m.p. 153-154° C.                                                       (ethanol)                                            3-(2)  5-OCH.sub.3                                                                            2        oil                                                                           IR.sub.Max.sup.Nujol (cm.sup.-1): 1750               4-(2)  6-SO.sub.3 Na                                                                          2        m.p. >300° C.                                                          (washed with isopropyl alcohol)                                               IR.sub.Max.sup.Nujol (cm.sup.-1): 1750, 1730         5-(2)  H        1        m.p. 108-108.5° C.                                                     (ethyl acetate - hexane)                             ______________________________________                                         *A position of 5methoxymethyl-2-oxazolidon-3-yl group in naphthalene ring

EXAMPLE 6

A mixture of 4.63 g of N-ethoxycarbonyl-2-naphthylamine, 4.2 g of2-(butoxymethyl)oxirane and 0.22 g of triethylamine is stirred at 100°to 105° C. for 1.5 hours. The reaction mixture is cooled, and thecrystalline precipitate are collected by filtration, treated withcharcol and recrystallized from ethyl acetate-isopropyl ether-hexane.4.7 g of 3-(2-naphthyl)-5-tert.butoxymethyl-2-oxazolidone are obtained.

m.p. 112.5°-113.0° C.

EXAMPLE 7

(1) 19.69 g of triethylamine are added to a solution of 10.23 g of1-amino-3-methoxy-2-propanol in 100 ml of tetrahydrofuran. After themixture is cooled, a solution of 16.60 g of benzyloxycarbonyl chloridein 50 ml of tetrahydrofuran is added dropwise thereto for 30 minutes.The mixture is stirred at room temperature for one hour. The reactionmixture is diluted with ethyl acetate, washed with water and dried. Theresidue is purified by silica gel column chromatography [solvent: ethylacetate-hexane (2:1)]. 13.2 g of1-benzyloxycarbonylamino-3-methoxy-2-propanol are obtained as colorlessoil. ##STR24##

(2) 10.2 g of the product obtained in the paragraph (1) are dissolved in200 ml of tetrahydrofuran, and 1.624 g of sodium hydride (60% dispersionin oil) are added thereto. The mixture is stirred at room temperaturefor one hour. Water is added to the reaction mixture and the mixture isextracted with chloroform. The extract is condensed and the residue ispurified by silica gel column chromatography [solvent: ethylacetate-hexane (3:1)]. 3.36 g of 5-methoxymethyl-2-oxazolidone areobtained as colorless oil. ##STR25##

(3) 1.2 g of sodium methoxide are added to a mixture of 38.44 g of1-amino-3-methoxy-2-propanol and 64.78 g of diethyl carbonate. Themixture is stirred at 100° C. for 2.5 days. An excess diethyl carbonateis removed from the mixture. The residue is dissolved in 50 ml ofanhydrous tetrahydrofuran, and 1.4 g of 63% of sodium hydride are addedthereto. The mixture is stirred overnight at room temperature. 4 ml ofacetic acid are added to the reaction mixture, and the mixture isstirred at room temperature for 3 hours. Insoluble materials arefiltered off. The filtrate is condenced and the residue is distilledunder reduced pressure. 42.38 g of 5-methoxymethyl-2-oxazolidone areobtained as colorless oil.

The physico-chemical properties of this product are identical to thoseof the compound obtained in the paragraph (2).

(4) 6.10 g of activated copper powder and 2.76 g of sodium carbonate areadded to a mixture of 5.24 g of the product obtained in the paragraph(2) or (3) and 4.14 g of 2-bromonaphthalene. The mixture is stirred at200° C. for 3 hours. After the mixture is cooled, ethyl acetate is addedthereto and insoluble materials are filtered off. The filtrate isevaporated under reduced pressure to remove the solvent. The residue ispurified by silica gel column chromatography [solvent: ethylacetate-hexane (2:3)]. 2.36 g of5-methoxymethyl-3-(2-naphthyl)-2-oxazolidone are obtained as colorlessneedles.

The physico-chemical properties of this product are identical to thoseof the compound obtained in Example 1.

EXAMPLES 8 AND 9

The corresponding starting compounds are treated in the same manner asdescribed in Example 7-(4) to give the compounds shown in Table 5.

                  TABLE 5                                                         ______________________________________                                         ##STR26##                                                                     ##STR27##                                                                    Ex.   Compound (I-g)                                                          No.   R.sup.1        Melting Point                                            ______________________________________                                        8     OCH.sub.3      142-143.5° C.                                                          (ethyl acetate - isopropyl ether)                               ##STR28##     144-146° C. (ethyl acetate)                       ______________________________________                                    

EXAMPLE 10

(1) 100 g of 1,2-epoxypropyl tert.-butyl ether are added dropwise to 500ml of conc. aqueous ammonia under ice-cooling and the mixture is stirredat room temperature for 20 hours. The reaction mixture is evaporatedunder reduced pressure to remove the aqueous ammonia. Chloroform isadded to the residue. The mixture is dried with potassium carbonate.Insoluble materials are filtered off and the filtrate is evaporated toremove the solvent. The residue is distilled under reduced pressure.49.3 g of 1-amino-3-tert.-butoxy-2-propanol are obtained.

b.p. 109°-110° C./8 mmHg.

m.p. 41°-43° C.

(2) A mixture of 49.3 g of the product obtained in the paragraph (1),4.91 g of diethyl carbonate and 0.18 g of sodium methoxide is heated at50° C. for 3 hours. About 40 ml of ethanol which is produced during thereaction are evaporated. After the reaction is completed, the mixture isevaporated under reduced pressure to remove excess diethyl carbonate.The residue is cooled, and the crystalline precipitates are washed withhexane. 55.4 g of 5-tert.-butoxymethyl-2-oxazolidone are obtained ascolorless crystals.

m.p. 57°-65° C.

(3) 1.1 g of the product obtained in the paragraph (2) and 1.0 g of2-benzyloxy-6-bromonaphthalene are treated in the same manner asdescribed in Example 7-(4). 0.73 g of3-(6-benzyloxy-2-naphthyl)-5-tert.-butoxymethyl-2-oxazolidone isobtained as colorless crystals.

m.p. 151.5°-152° C. (ethyl acetate-isopropyl ether).

EXAMPLE 11

(1) 21.0 g of tosyl chloride are added portionwise to a mixture of 14.4g of (R)-α,β-isopropylidene glycerol and 60 ml of pyridine underice-cooling. The mixture is stirred for 4 hours. 50 ml of water areadded to the mixture under ice-cooling. The mixture is stirred at roomtemperature for 10 minutes. The reaction mixture is extracted withdiethyl ether, the extract is washed with water and dried. The solventis removed by evaporation under reduced pressure. 29.5 g of(4S)-2,2-dimethyl-4-tosyloxymethyl-1,3-dioxolane are obtained as palebrown oil. ##STR29##

Mass (m/z): 276 (M⁺ -15), 155, 101, 91 (base), 43.

(2) A mixture of 9.51 g of the product obtained in the paragraph (1),5.25 g of 6-(cyclopropylmethoxy) naphthylamine, 5.54 g of sodium iodide,6.2 g of sodium bicarbonate and 42 ml of hexamethylphosphoric triamideis stirred at 120° C. for 11 hours. The reaction mixture is poured intowater and extracted with ethyl acetate. The extract is washed withwater, dried and evaporated. The residue is purified by silica gelcolumn chromatography [solvent: ethyl acetate-hexane (1:5)] andrecrystallized from ethyl acetate-hexane. 5.88 g of(4R)-4-[6-(cyclopropylmethoxy)-2-naphthylaminomethyl]-2,2-dimethyl-1,3-dioxolaneare obtained as pale yellow scales.

m.p. 108.5°-109.0° C. ##STR30##

(3) A mixture of 8.09 g of the product obtained in the paragraph (2), 35ml of 1N-hydrochloric acid and 80 ml of tetrahydrofuran is stirred at60° C. for 2 hours. The reaction mixture is condensed under reducedpressure. The residue is basified with aqueous sodium bicarbonatesolution and extracted with ethyl acetate. The extract is washed withwater, dried and evaporated under reduced pressure to remove thesolvent. The residue is recrystallized from ethyl acetatehexane. 6.93 gof (2R)-3-(6-cyclopropylmethoxy-2-naphthylamino)-1,2-propandiol areobtained as pale brown scales.

m.p. 138.0°-138.5° C. ##STR31##

(4) A mixture of 1.36 g of the product obtained in the paragraph (3),670 mg of diethyl carbonate, one ml of toluene and 50 mg of sodiummethoxide is stirred at 150° C. for one hour. The reaction mixture isevaporated under reduced pressure to remove the solvent. One drop ofacetic acid is added to the residue. The residue is purified by silicagel column chromatography [solvent; chloroform-ethyl acetate (1:1 to1:3)] and recrystallized from ethyl acetate-hexane. 1.06 g of(5R)-3-(6-cyclopropylmethoxy-2-naphthyl)-5-hydoroxymethyl-2-oxazolidoneare obtained as colorless needles

m.p. 181.5°-182.5° C. ##STR32##

EXAMPLE 12

Amixture of 626 mg of(5R)-3-(6-cyclopropylmethoxy-2-naphthyl)-5-hydroxymethyl-2-oxazolidone,114 mg of sodium hydride (63% dispersion in oil) and 5 ml ofdimethylformamide is stirred at room teperature for 10 minutes. 350 mgof methyl iodide are added to the mixture, and the mixture is stirred atroom temperature for 2 hours. 0.1 ml of acetic acid is added to thereaction mixture. The mixture is poured into water and extracted withethyl acetate, and the extract is washed with water, dried andevaporated under reduced pressure to remove the solvent. The residue ispurified by silica gel column chromatography [solvent: chloroform-ethylacetate (2:1)] and recrystallized from ethyl acetate-hexane. 501 mg of(5R)-3-(6-cyclopropylmethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidoneare obtained as colorless scales.

m.p. 119.0°-119.5° C. ##STR33##

EXAMPLE 13

6.99 g of 5-methoxymethyl-3-(7-nitro-2-naphthyl)-2-oxazolidone aresuspended in 140 ml of acetic acid, and 2.1 g of 10% palladium-carbonare added thereto. The mixture is subjected to catalytic hydrogenationunder atomospheric pressure at room temperature. The reaction mixture isfiltered with celite and the filtrate is evaporated under reducedpressure. The residue is extracted with ethyl acetate and the extract iswashed, dried and condensed. The residue is purified by silica gelcolumn chromatography [solvent: ethyl acetate-hexane (2:1 to 3:1)], andresidue is recrystallized from ethyl acetate-isopropyl ether to give4.96 g of 3-(7-amino-2-naphthyl)-5-methoxymethyl-2-oxazolidone.

m.p. 98°-99° C.

EXAMPLES 14 AND 15

A solution of 0.97 g of sodium nitrite is 6 ml of water is addeddropwise at 0° to 5° C. to a mixture of 3.47 g of3-(7-amino-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 6 ml of water and3.3 ml of conc. hydrochloric acid. After the mixture is stirred for afew minutes, 100 ml of methanol are added thereto. The mixture isstirred at room temperature for 7 hours and then allowed to stand in arefrigerator overnight. The reaction mixture is extracted with ethylacetate and the extract is washed and dried. The aqueous layer isfurther extracted with chloroform and the extract is dried. The residue(1.88 g) is purified by silica gel column chromatography [solvent: ethylacetate-hexane (1:1)].5-methoxymethyl-3-(7-methoxy-2-naphthyl)-2-oxazolidone [Example 14, m.p.95.5°-96.5° C. (recrystallized from ethyl acetate-hexane)] and3-(7-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone [Example 15 ,m.p. 155°-157° C. (recrystallized from ethyl acetate-hexane)] areobtained.

EXAMPLE 16

1.0 ml of thionyl chloride is added to a suspension of 3.0 g of sodium6-(5-methoxymethyl-2-oxazolidone-3-yl)-2-naphthylsulfonate in 24 ml ofdimethylformamide under ice-cooling. The mixture is stirred at roomtemperature for one hour. After ice-cooling, the mixture is poured intoice-water and extracted with ethyl acetate. The extract is washed, driedand evaporated under reduced pressure to remove the solvent to give 2.9g of pale brown foam.

The foam is dissolved in 50 ml of tetrahydrofuran and 10 ml of conc.aqueous ammonium hydroxide solution are added thereto. The mixture isstirred at room temperature for 2 hours. 200 ml of water are added tothe mixture. The mixture is stirred for a minute and allowed to standovernight at room temperature. Crystalline precipitates are collectedand recrystallized from ethanol. 1.97 g of3-(6-aminosulfonyl-2-naphthyl)-5-methoxymethyl-2-oxazolidone areobtained as colorless powder.

m.p. 166°-168° C.

EXAMPLE 17

18.9 g of 3-(6-benzyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone isdissolved in 700 ml of tetrahydrofuran and 10.0 g of 10% ofpalladium-carbon are added thereto. The mixture is subjected tocatalytic hydrogenation under atmospheric pressure at room temperaturefor 10 hours. The catalyst is filtered off, and the filtrate isevaporated under reduced pressure to remove the solvent. The residue isrecrystallized from ethanol-tetrahydrofuran-isopropyl ether. 11.2 g of3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone are obtained ascolorless needles.

m.p. 192°-193° C.

EXAMPLE 18

30.6 g of 3-(6-benzyloxy-2-naphthyl)-5-tert.-butoxymethyl-2-oxazolidoneare treated in the same manner as described in Example 17. 22.7 g of3-(6-hydroxy-2-naphthyl)-5-tert.-butoxymethyl-2-oxazolidone are obtainedas colorless crystals.

m.p. 177°-178° C. (tetrahydrofuran-isopropyl ether-hexane).

EXAMPLE 19

5.06 g of potassium carbonate and 2 ml of ethyl iodide are added to asolution of 2.0 g of3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone in 25 ml ofdimethyl formamide. The mixture is stirred for 4 hours at roomtemperature. The reaction mixture is diluted with ethyl acetate, washedwith water and dried. The residue is recrystallized from ethylacetate-isopropyl ether. 1.89 g of3-(6-ethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone are obtained ascolorless plates.

m.p. 129.5°-130.5° C.

EXAMPLES 20 to 46

The corresponding starting compounds are treated in the same manner asdescribed in Example 19 to give a compounds shown in Table 6.

    ______________________________________                                         ##STR34##                                                                     ##STR35##                                                                    Ex.  Compound (I-i)                                                           No.  R.sup.1         R.sup.2    Melting Point                                 ______________________________________                                        20   O(CH.sub.2).sub.2 CH.sub.3                                                                    OCH3       94.5-95.5° C.                                                          (ethyl acetate -                                                              hexane)                                       21   OCH(CH.sub.3).sub.2                                                                           OCH3       111.5-116° C.                                                          (ethyl acetate -                                                              hexane)                                       22   O(CH.sub.2).sub.3 CH.sub.3 80.5-81° C.                                                            (ethyl acetate -                                                              hexane)                                       23   OCH(CH.sub.3)CH.sub.2 CH.sub.3                                                                           79-80° C.                                                              (ethyl acetate -                                                              hexane)                                       24    OCH.sub.2 CH(CH.sub.3).sub.2                                                                            114-114.5° C.                                                          (ethyl acetate -                                                              hexane)                                       25   O(CH.sub.2).sub.4 CH.sub.3 82-83° C.                                                              (ethyl acetate -                                                              hexane)                                       26   O(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                                     88-89° C.                                                              (ethyl acetate -                                                              hexane)                                       27                                                                                  ##STR36##                 120-121° C. (ethyl acetate -                                           isopropyl ether)                              28                                                                                  ##STR37##                 113-125° C. (ethyl acetate -                                           isopropyl ether)                              29   O(CH.sub.2).sub.2 OH       120-121° C.                                                            (ethyl acetate -                                                              isopropyl ether)                              30   O(CH.sub.2).sub.3 OH       87.5-88.5° C.                                                          (ethyl acetate -                                                              hexane)                                       31   O(CH.sub.2).sub.2 OCH.sub.3                                                                              102-103° C.                                                            (ethyl acetate -                                                              hexane)                                       32   O(CH.sub.2).sub.2 OC.sub.2 H.sub.5                                                                       82- 84° C.                                                             (ethyl acetate -                                                              hexane)                                       33   OCH.sub.2 CN    OCH3       97-98° C.                                                              (ethyl acetate -                                                              hexane)                                       34   O(CH.sub.2).sub.3 CN       84.5-86° C.                                                            (ethyl acetate -                                                              hexane)                                       35   O(CH.sub.2).sub.2 N(CH.sub.3).sub.2                                                                      207-207.5° C.                                                          Hydrochloride                                                                 (methanol -                                                                   diethyl ether)                                36   OCH.sub.2 CONH.sub.2       176.5-177.5° C.                                                        (ethyl acetate -                                                              hexane)                                       37   OCH(CH.sub.3)CO.sub.2 CH.sub.3                                                                           91-95° C.                                                              (ethyl acetate -                                                              hexane)                                       38   OCH.sub.2 CHCH.sub.2       108.5-109.5° C.                                                        (ethyl acetate -                                                              hexane)                                       39   O(CH.sub.2).sub.2 CHCH.sub.2                                                                             90-92° C.                                                              (ethyl acetate -                                                              hexane)                                       40   OCH.sub.2 CHC(CH.sub.3).sub.2                                                                            105.5-107° C.                                                          (ethyl acetate -                                                              hexane)                                       41   OCH.sub.2 CCH              99.5-100.5° C.                                                         (ethyl acetate -                                                              hexane)                                       42   O(CH.sub.2).sub.2 OCOCH.sub.3                                                                            89-92° C.                                                              (ethyl acetate -                                                              hexane)                                       43   O(CH.sub.2).sub.2 SCH.sub.3                                                                              81-84° C.                                                              (ethyl acetate -                                                              hexane)                                       44   OCON(CH.sub.3).sub.2       107-108° C.                                                            (ethyl acetate -                                                              hexane)                                       45   O(CH.sub.2).sub.2 CH.sub.3                                                                    OC(CH.sub.3).sub.3                                                                       121-122° C.                                                            (ethyl acetate -                                                              hexane)                                       46   O(CH.sub.2).sub.3 CH.sub.3 123-123.5° C.                                                          (ethyl acetate -                                                              hexane)                                       ______________________________________                                    

EXAMPLE 47

A mixture of 720 mg of3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 5 ml ofacrylonitrile, 5 ml of acrylonitrile, 5 ml of tetrahydrofuran and 0.1 mlof methanolic 40% benzyltrimethylammonium hydroxide solution is refluxedfor 2 days. The reaction mixture is condensed under reduced pressure todryness. The residue is extracted with ethyl acetate, and the extract iswashed with water, dried and condensed under reduced pressure. Theresidue is purified by silica gel column chromatography [solvent:chloroform-methanol (20:1)] and recrystallized from ethylacetate-hexane. 410 mg of3-(6-cyanoethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone are obtainedas colorless scale.

m.p. 110°-112° C.

EXAMPLES 48 to 50

The corresponding starting compounds are treated in the same manner asdescribed in Example 47 to give the compounds shown in Table 7.

                  TABLE 7                                                         ______________________________________                                         ##STR38##                                                                     ##STR39##                                                                    Compound (I-i)                                                                Ex. No.                                                                              R.sup.1        R.sup.2   Melting Point                                 ______________________________________                                        48     O(CH.sub.2).sub.2 CN                                                                         O(CH.sub.3).sub.3                                                                       175.5-177° C.                                                          (ethyl acetate)                               49     O(CH.sub.2).sub.2 CO.sub.2 CH.sub.3                                                          OCH.sub.3 111-112° C.                                                            (ethyl acetate -                                                              hexane)                                       50     O(CH.sub.2).sub.2 CO.sub.2 C.sub.2 H.sub.5                                                   OCH.sub.3 91.5-93° C.                                                            (ethyl acetate -                                                              hexane)                                       ______________________________________                                    

EXAMPLE 51

A mixture of 950 mg of3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 310 mg of ethylisocyanate, 15 ml of methylene chloride, 10 ml of tetrahydrofuran andone drop of triethylamine is stirred at room temperature for 4 hours.1.5 g of ethyl isocyanate are further added to the mixture, and themixture is refluxed for 3 hours. The reaction mixture is condensed underreduced pressure. The residue is dissolved in ethyl acetate and washedwith water treated with charcol and dried. The solvent is removed byevaporation under reduced pressure. The residue is recrystallized fromethyl acetate-isopropyl ether. 800 mg of3-(6-ethylaminocarbonyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone areobtained as colorless prisms

m.p. 126.5°-127.5° C.

EXAMPLE 52

A mixture of 2.0 g of3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone and 10 ml ofacetic anhydride is refluxed for one hour. The reaction mixture isevaporated to remove an excess acetic anhydride. The residue isrecrystallized from ethyl acetate-isopropyl ether. 2.25 g of3-(6-acetyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone are obtained ascolorless crystals.

m.p. 110°-112.5° C.

EXAMPLE 53

1.07 g of m-chloroperbenzoic acid are gradually added at roomtemperature to a mixture of 1.88 g of5-methoxymethyl-3-[6-(methylthioethoxy)-2-naphthyl]-2-oxazolidone and100 ml of methylene chloride. The mixture is stirred at room temperaturefor one hour. The reaction mixture is washed with 10% aqueous sodiumhydroxide solution and water, and then dried. The solvent is removed byevaporation under reduced pressure. The residue is purified by silicagel column chromatography [solvent: chloroform-methanol (30:1)] andrecrystallized from ethyl acetate-tetrahydrofuran-isopropyl ether. 1.21g of5-methoxymethyl-3-[6-(methylsulfinylethoxy)-2-naphthyl]-2-oxazolidoneare obtained as colorless prisms.

m.p. 133°-141° C.

EXAMPLE 54

1.65 g of m-chloroperbenzoic acid are gradually added at roomtemperature to a mixture of 1.20 g of5-methoxymethyl-3-[6-(methylthioethyloxy)-2-naphthyl]-2-oxazolidone and40 ml of methylene chloride. The mixture is stirred at room temperaturefor 3 hours. The reaction mixture is washed with 10% aqueous sodiumhydroxide solution and water and then dried. The solvent is removed byevaporation under reduced pressure. The residue is purified by silicagel column chromatography [solvent: chloroform-ethyl acetate (1:1)] andthen recrystallized from ethanol-tetrahydrofuran-isopropyl ether. 0.73 gof5-methoxymethyl-3-[6-(methylsulfonylethyloxy)-2-naphthyl]-2-oxazolidoneare obtained as colorless needles.

m.p. 128°-129° C.

EXAMPLE 55

10 ml of trifluoroacetic acid are added to 3.36 g of3-(2-naphthyl)-5-tert.-butoxymethyl-2-oxazolidone under ice-cooling. Themixture is stirred at room temperature for one hour. The reactionmixture is evaporated under reduced pressure to remove trifluoroaceticacid. The residue is recrystallized fromethanol-dimethylformamide-isopropyl ether. 2.16 g of5-hydroxymethyl-3-(2-naphthyl)-2-oxazolidone are obtained as colorlesscrystals

m.p. 174°-174.5° C.

EXAMPLES 56 to 58

The corresponding starting compounds are treated in the same manner asdescribed in Example 55 to give compounds shown in Table 8.

                  TABLE 8                                                         ______________________________________                                         ##STR40##                                                                     ##STR41##                                                                    Compound (I-k)                                                                Ex. No. R.sup.1     Melting Point                                             ______________________________________                                        56      O(CH.sub.2).sub.2 CH.sub.3                                                                149-150° C.                                                            (ethyl acetate - isopropyl ether)                         57      O(CH.sub.2).sub.3 CH.sub.3                                                                127-130° C.                                                            (ethyl acetate - isopropyl ether)                         58      O(CH.sub.2).sub.2 CN                                                                      122-125° C.                                                            (ethyl acetate - isopropyl ether)                         ______________________________________                                    

EXAMPLE 59

A mixture of 8.5 g of methylsulfonyl chloride and 120 ml of methylenechloride is added dropwise to a suspension of 12.0 g of5-hydroxymethyl-3-(2-naphthyl)-2-oxazolidone, 240 ml of methylenechloride and 10.0 g of triethylamine under ice-cooling. The mixture isstirred at room temperature for 3 hours. A mixture of 1.0 g ofmethylsulfonyl chloride and 50 ml of tetrahydrofuran is added dropwiseto the mixture, and the mixture is stirred at room temperature for 2hours. The reaction mixture is washed with water. The extract is dried,and then evaporated under reduced pressure to remove the solvent. Theresidue is recrystallized from isopropyl ether. 14.7 g of5-methylsulfonyloxymethyl-3-(2-naphthyl)-2-oxazolidone are obtained ascolorless crystals.

m.p. 169°-172° C.

EXAMPLE 60

A mixture of 3.0 g of5-methylsulfonyloxymethyl-3-(2-naphthyl)-2-oxazolidone, 120 ml of anaqueous 40% methylamine solution, 100 ml of tetrahydrofuran and 50 ml ofdimethylformamide is stirred at room temperature in a sealed tube for 2days. The reaction mixture is evaporated under reduced pressure toremove the excess methylamine and tetrahydrofuran. The mixture isextracted with ethyl acetate, and the extract is washed with water,dried evaporatedunder reduced pressure to remove the solvent. Theresidue is purified by silica gel column chromatography [solvent:chloroform-methanol (20:1)] and recrystallized from ethylacetate-hexane. 1.12 g of5-methylaminomethyl-3-(2-naphthyl)-2-oxazolidone are obtained ascolorless crystals.

m.p. 76.5°-78.0° C.

EXAMPLE 61

A mixture of 11.6 g of5-methylsulfonyloxymethyl-3-(2-naphthyl)-2-oxazolidone, 230 ml ofdimethylformamide, 4.84 g of sodium azide and 23 ml of water is stirredat 80° C. for 9 hours. The reaction mixture is poured into water,extracted with ethyl acetate, and the extract is washed with water,dried and evaporated under reduced pressure to remove the solovent. Theresidue is recrystallized from ethyl acetate-hexane. 8.62 g of3-(2-naphthyl)-5-triazomethyl-2-oxazolidone are obtained as colorlesscrystals.

m.p. 115.0°-116.5° C.

EXAMPLE 62

8.35 g of 3-(2-naphthyl)-5-triazomethyl-2-oxazolidone are dissolved in amixture of 100 ml of tetrahydrofuran and 100 ml of acetic acid. 2.0 g of10% palladium-carbon are added to the solution. The mixture is subjectedto catalytic hydrogenation at room temperature under atmosphericpressure. After the palladium-carbon is removed, the filtrate isevaporated under reduced pressure to remove the solvent. The residue isbasified with an aqueous sodium bicarbonate solution. Crystallineprecipitates are collected by filtration, and washed with water. Themixture is purified by silica gel column chromatography [solvent:chloroform-methanol (40:1 to 8:1)] and recrystallized fromethanol-isopropyl ether-hexane. 4.90 g of5-aminomethyl-3-(2-naphthyl)-2-oxazolidone are obtained as colorlesscrystals.

m.p. 112°-114° C.

EXAMPLE 63

A mixture of 1.8 g of 5-aminomethyl-3-(2-naphthyl)-2-oxazolidone, 36 mlof chloroform, 1.5 ml of acetic anhydride and 1.5 ml of pyridine isstirred at room temperature for one hour. The reaction mixture is washedwith water, dried and evaporated under reduced pressure to remove thesolvent. The residue is recrystallized from ethyl acetate-isopropylether. 1.56 g of 5-acetylaminomethyl-3-(2-naphthyl)-2-oxazolidone areobtained as colorless crystals.

m.p. 152°-154° C.

EXAMPLE 64

(1) A mixture of 2.0 g of3-(6-benzyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 20 ml ofethanol, 4 ml of water and 1.08 g of potassium hydroxide is stirred at100° C. for one hour. The reaction mixture is evaporated under reducedpressure to remove the ethanol. The residue is extracted with ethylacetate, and the extract is washed with water, dried and evaporatedunder reduced pressure to remove the solvent. The residue isrecrystallized from ethyl acetate-hexane to give 1.64 g ofN-(3-methoxy-2-hydroxypropyl)-6-benzyloxy-2-naphthylamine as colorlessneedles.

m.p. 103°-104° C.

(2) A mixture of 3.53 g of ethyl chloroformate and 5 ml of methylenechloride is added dropwise to a mixture of 10.0 g of the productobtained in the paragraph (1), 70 ml of methylene chloride, 70 ml ofwater and 4.98 g of sodium bicarbonate under ice-cooling. The mixture isstirred at room temperature for 1.5 hours. A mixture of 0.35 g of ethylchloroformate and 2 ml of methylene chloride is added to the mixture,and the mixture is further stirred at room temperature for 4 hours.Organic layer is separated from the reaction mixture. The aqueous layeris extracted with methylene chloride and conbined with the organiclayer. The conbined solution is dried and then evaporated under reducedpressure to remove the solvent. The residue is purified by silica gelcolumn chromatography [solvent: ethyl acetate-hexane (1:1)]. 12.66 g ofN-ethoxycarbonyl-N-(3-methoxy-2-hydroxypropyl)-6-benzyloxy-2-naphthylamineare obtained as colorless oil. ##STR42##

Mass (m/z): 409 (M⁺), 318, 91 (base).

(3) A mixture of 4.68 g of pyridine and 10 ml of tetrahydrofuran isadded dropwise to a mixture of 12.12 g of the product obtained in theparagraph (2), 120 ml of tetrahydrofuran and 11.5 g of(2S)-1-(2-naphthylsulfonyl)pyrrolidin-2-carbonyl chloride underice-cooling. The mixture is stirred at room temperature for 3.5 hours.The reaction mixture is diluted with 500 ml of ethyl acetate, washedwith 5% hydrochloric acid and water, dried and evaporated to remove thesolvent. The residue is purified by silica gel column chromatography[solvent: ethyl acetate-hexane (2:3)]. 9.48 g ofN-ethoxycarbonyl-N-{(2R)-3-methoxy-2-[(2S)-1-(2-naphthylsulfonyl)pyrrolidin-2-carbonyloxy]-propyl}-6-benzyloxy-2-naphthylamine(Product A) and 9.28 g ofN-ethoxycarbonyl-N-{(2S)-3-methoxy-2-[(2S)-1-(2-naphthylsulfonyl)pyrrolidin-2-carbonyloxy]-propyl}-6-benzyloxy-2-naphthylamine(Product B) are obtained as colorless oils.

Product A ##STR43## Product B ##STR44##

(4) A mixture of 8.95 g of Product A obtained in paragrapyh (3), 2.57 gof sodium hydroxide, 100 ml of ethanol and 20 ml of water is stirred at100° C. for one hour. The reaction mixture is evaporated under reducedpressure to remove the solvent, and water is added to the residue. Themixture is extracted with ethyl acetate. The extract is washed withwater, dried and condenced. Hexane is added to the residue, andcrystalline precipitates are collected by filtration. 3.76 g ofN-[(2R)-3-methoxy-2-hydroxypropyl]-6-benzyloxy-2-naphthylamine areobtained as colorless crystals.

m.p. 105°-106° C. ##STR45##

(5) A mixture of 3.65 g of the product obtained in the paragraph (4), 70ml of dry methylene chloride, 3.51 g of carbonyldiimidazol and 0.14 g ofdiisopropylethylamine is stirred at room temperature for 2 hours. Thereaction mixture is washed with 5% hydrochloric acid. The aqueous layeris extracted with ethyl acetate, and the extract is conbined with theorganic layer. The mixture is dried and evaporated under reducedpressure to remove the solvent. The residue is recrystallized from ethylacetate to give 3.60 g of(5R)-3-(6-benzyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone ascolorless scales.

m.p. 150°-150.5° C. ##STR46##

EXAMPLE 65

(1) 9.2 g ofN-ethoxycarbonyl-N-{(2S)-3-methoxy-2-[(2S)-1-(2-naphthylsulfonyl)-2-pyrrolidinylcarbonyloxy]propyl}-6-benzyloxy-2-naphthylamineare treated in the same manner as described in Example 64-(4). 3.76 g ofN-[(2S)-3-methoxy-2-hydroxypropyl]-6-benzyloxy-2-naphthylamine areobtained as colorless needles.

m.p. 105°-106° C. ##STR47##

(2) 3.62 g of the product obtained in the paragraph (1) are treated inthe same manner as described in Example 64-(5). 3.55 g of(5S)-3-(6-benzyloxy-2-naphthy)-5-methoxymethyl-2-oxazolidone ascolorless needles.

m.p. 149.5°-150.5° C. ##STR48##

EXAMPLE 66

A mixture of 16.9 g of(5R)-3-(6-benzyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 8.50 g of10% palladium-carbon and 400 ml of tetrahydrofuran are hydrogenated at45° to 50° C. for 2 hours under atmospheric pressure. Insolublematerials are filtered off. The filtrate is evaporated under reducedpressure to remove the solvent. The residue is recrystallized fromtetrahydrofuran-isopropyl ether. 11.5 g of(5R)-3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone are obtainedas colorless prisms.

m.p. 190°-191° C. ##STR49##

EXAMPLE 67

15.0 g of (5S)-3-(6-benzyloxy-2-naphthyl)-5-methoxymethyl-2-oxazolidoneare treated in the same manner as described in Example 66. 10.3 g of(5S)-3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone are obtainedas colorless prisms.

m.p. 190°-191° C. ##STR50##

EXAMPLE 68

A mixture of 2.38 g of(5R)-3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidone, 1.83 g ofcyclopropylmethyl bromide, 3.55 g of potassium carbonate and 30 ml ofdimethylformamide is stirred at 50° C. for 7 hours. The reaction mixtureis poured into water, extracted with ethyl acetate. The extract iswashed with water, dried and evaporated under reduced pressure to removethe solvent. The residue is purified by silica gel column chromatography[solvent: ethyl acetate-chloroform (1:10)] and recrystallized from ethylacetate-hexane. 2.51 g of(5R)-3-(6-cyclopropylmethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidoneare obtained as colorless scales.

m.p. 120.5°-121° C. ##STR51##

EXAMPLE 69

3.69 g of (5S)-3-(6-hydroxy-2-naphthyl)-5-methoxymethyl-2-oxazolidoneand 2.84 g of cyclopropylmethyl bromide are treated in the same manneras described in Example 68. 4.07 g of(5S)-3-(6-cyclopropylmethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidoneas colorless scales.

m.p. 119°-119.5° C. ##STR52##

What is claimed is:
 1. A method for treatment or prophylaxis ofdepressive conditions in a warm-blood animal which comprisesadministering to said warm-blood animal a pharmaceutically effectiveamount of a naphthyloxazolidone compound of the formula:wherein R¹ is ahydrogen atom, a hydroxy group, a nitro group, an amino group, a sulfogroup, an aminosulfonyl group, a lower alkenyloxy group, a loweralkynyloxy group, a mono or di(lower alkyl) aminocarbonyloxy group, alower alkanoyloxy group or a lower alkoxy group which is unsubstitutedor has a substituent selected from the group consisting of a phenylgroup, a cycloalkyl group of 3 to 6 carbon atoms, a tetrahydrofurylgroup, a hydroxy group, a lower alkoxy group, a cyano group, a di(loweralkyl)amino group, an aminocarbonyl group, a lower alkoxycarbonyl group,a lower alkanoyloxy group, a lower alkylthio group, a loweralkylsulfinyl group and a lower alkylsulfonyl group; and R² is a loweralkoxy group; or a pharmaceutically acceptable salt thereof.
 2. A methodin accordance with claim 1, wherein R¹ is a hydrogen atom, a hydroxygroup, a lower alkenyloxy group, a lower alkanoyloxy group or a loweralkoxy group which is unsubstituted or has a substituent selected fromthe group consisting of a cycloalkyl group of 3 to 6 carbon atoms, ahydroxy group, a lower alkyloxy group, a cyano group, a loweralkanoyloxy group and a lower alkylthio group.
 3. A method in accordancewith claim 1 in which R¹ is at the 6-position of the naphthalene ringand the 5-substituted-2-oxazolidon-3-yl group is at the 2-position ofthe naphthalene ring.
 4. A method in accordance with claim 3, wherein R¹is a lower alkenyloxy group or a lower alkoxy group which isunsubstituted or has a substituent selected from the group consisting ofa cycloalkyl group of 3 to 6 carbon atoms, a hydroxy group, a loweralkoxy group, a cyano group, a lower alkanoyloxy group and a loweralkylthio group.
 5. A method in accordance with claim 1, wherein saidnaphthyloxazolidone compound is(5R)-3-(6-cyclopropylmethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidoneor a pharmaceutically acceptable salt thereof. 6.(5R)-3-(6-cyclopropylmethoxy-2-naphthyl)-5-methoxymethyl-2-oxazolidoneor a pharmaceutically acceptable salt thereof.